title: Spinal actions of lipoxin A4 and 17(R)-resolvin D1 attenuate inflammation-induced mechanical hypersensitivity and spinal TNF release.
abstract: Lipoxins and resolvins have anti-inflammatory and pro-resolving actions and accumulating evidence indicates that these lipid mediators also attenuate pain-like behavior in a number of experimental models of inflammation and tissue injury-induced pain. The present study was undertaken to assess if spinal administration of lipoxin A4 (LXA4) or 17 (R)-resolvin D1 (17(R)-RvD1) attenuates mechanical hypersensitivity in the carrageenan model of peripheral inflammation in the rat. Given the emerging role of spinal cytokines in the generation and maintenance of inflammatory pain we measured cytokine levels in the cerebrospinal fluid (CSF) after LXA4 or 17(R)-RvD1 administration, and the ability of these lipid metabolites to prevent stimuli-induced release of cytokines from cultured primary spinal astrocytes. We found that intrathecal bolus injection of LXA4 and17(R)-RvD1 attenuated inflammation-induced mechanical hypersensitivity without reducing the local inflammation. Furthermore, both LXA4 and 17(R)-RvD1 reduced carrageenan-induced tumor necrosis factor (TNF) release in the CSF, while only 17(R)-RvD1attenuated LPS and IFN-γ-induced TNF release in astrocyte cell culture. In conclusion, this study demonstrates that lipoxins and resolvins potently suppress inflammation-induced mechanical hypersensitivity, possibly by attenuating cytokine release from spinal astrocytes. The inhibitory effect of lipoxins and resolvins on spinal nociceptive processing puts them in an intriguing position in the search for novel pain therapeutics.
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden ; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.
authors.forename: Sally
authors.initials: S
authors.lastname: Abdelmoaty
authors.forename: Gustaf
authors.initials: G
authors.lastname: Wigerblad
authors.forename: Duygu B
authors.initials: DB
authors.lastname: Bas
authors.forename: Simone
authors.initials: S
authors.lastname: Codeluppi
authors.forename: Teresa
authors.initials: T
authors.lastname: Fernandez-Zafra
authors.forename: El-Sayed
authors.initials: el-S
authors.lastname: El-Awady
authors.forename: Yasser
authors.initials: Y
authors.lastname: Moustafa
authors.forename: Alaa El-Din S
authors.initials: Ael-D
authors.lastname: Abdelhamid
authors.forename: Ernst
authors.initials: E
authors.lastname: Brodin
authors.forename: Camilla I
authors.initials: CI
authors.lastname: Svensson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004487:Edema / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy* / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D044045:Lipoxins / Q000494:pharmacology*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044067:Receptors, Lipoxin / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D044045:Lipoxins; D044067:Receptors, Lipoxin; D014409:Tumor Necrosis Factor-alpha; C040527:lipoxin A4; C518399:resolvin D1; D004281:Docosahexaenoic Acids; D007371:Interferon-gamma; D020928:Mitogen-Activated Protein Kinases